Potential of Adjuvant-induced Lymphangiomas in Mice: Its Advantages as an Animal Model to Study Lymphatic Endothelial Cells

Abstract

Studies on the lymphatic system have made remarkable progress with the discovery of lymphatic endothelial cell-specific markers. To discover lymphatic endothelial cell-specific markers, we adopted a Freund's incomplete adjuvant (FIA) -induced lymphangioma model in rodents. The tumor was used as an antigen source of mouse lymphatic endothelium to produce monoclonal antibodies. We obtained LA102, which recognizes lymphatic endothelial cells, but not blood vessel endothelial cells. We found LA102 to be a homolog of mouse CD90.2 (Thy-1.2). Using LA102 and other specific markers for microvessels, including lectins, we have developed 3D-imaging techniques to characterize lymphatic networks to differentiate from blood vessels. This model has also been adopted to investigate the relationship between peritoneal mesothelium and lymphatic endothelium. At three days after FIA injection, simple squamous mesothelial cells became cuboidal and detached from each other to lose their polarity and formed multi layers. Various-sized fat droplets gradually fused with each other, and the fat-storing cells became large fat cells or formed large chimeric follicular structures. At four weeks or later, these cell masses formed tubular structures draining the fat out of the peritoneal cavity. Taking up fat (FIA) droplets, not only podoplanin⁺ mesothelial cells, but also bone marrow-derived macrophages and some interstitial mesenchymal cells were involved in tumorigenicity. We suggest a sequential change from mesothelial to lymphatic endothelial cells via fat-storing lymphangioma cells after FIA stimulation. These phenomena seem to be a defense mechanism, where mesothelial-endothelial transformation might occur via fat incorporation to drain the extrinsic adjuvant oil out of the peritoneal cavity. The significance of FIA-induced lymphangiomas and mesothelial cell diversity might be important for the interrelationship between fat cells and lymphatic endothelial cells.